The present invention relates to 3-phosphonate carbapenems having a sulfur containing substituent. The carbapenems are useful as antibiotics.
Mak et al., Tetrahedron Letters, Vol. 24, pp. 347-350 (1983), attempted to prepare certain 3-phosphonate carbapenems having a sulfur containing substituent but failed.
There is a continuing need for new antibiotics. Unfortunately, continued wide-scale use of an antibiotic often gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
The carbapenems of the present invention may be represented by the formula: ##STR1## wherein R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms, amino, --NHCO-alkyl wherein the alkyl moiety has 1 to 6 carbon atoms, hydroxy, alkoxy wherein the alkyl moiety has 1 to 6 carbon atoms, halo (i.e., fluoro, chloro, bromo or iodo), hydroxyalkyl wherein the alkyl moiety has 1 to 6 carbon atoms, carboxyl or trifluoromethyl;
R.sup.2 is alkyl having 1 to 6 carbon atoms, substituted alkyl wherein the alkyl moiety has 1 to 6 carbon atoms and is substituted with cyano, amino or ##STR2## phenyl, phenyl substituted with at least one substituent wherein the substituents are selected from amino, --NHCOCH.sub.3, --NHCH.dbd.NH, aminoalkyl wherein the alkyl moiety has 1 to 6 carbon atoms, nitro, halo (i.e. fluoro, chloro, bromo and iodo), alkyl having 1 to 6 carbon atoms and trifluoromethyl, pyrrolidinyl, N-substituted pyrrolidinyl wherein the substituent is selected from --CH.dbd.NH and ##STR3## 3-.DELTA.'-2-amino-pyrrolidinyl, piperidinyl, 3-.DELTA.'-2-amino-piperidinyl, and N,N-dimethylcarboxamidine; and PA0 R.sup.3 is hydrogen, a metal cation, alkyl having 1 to 6 carbon atoms, benzyl, substituted benzyl wherein the phenyl moiety of the benzyl group may be substituted with alkyl having 1 to 6 carbon atoms, chloro, fluoro or bromo, ##STR4## wherein the alkyl group has 1 to 6 carbon atoms, ##STR5## wherein the alkyl group has 1 to 6 carbon atoms, ##STR6## wherein R.sup.5 is hydrogen or alkyl having 1 to 6 carbon atoms; and M is a metal cation or H.sup.+. PA0 sodium(5R,6S)-2-cyanomethylthio-6-(R-1-hydroxyethyl)-3-methylphosphonyl-car bapenem; PA0 sodium(5R,6S)-2-phenylthio-6-(R-1-hydroxyethyl)-3-methylphosphonyl-carbapen em; PA0 sodium(5R,6S)-2-(2-aminoethanethio)-6-(R-1-hydroxyethyl)-3-methylphosphonyl -carbapenem; PA0 (5R,6S)-2-(2-formamidineethanethio)-6-(R-1-hydroxyethyl)-3-methylphosphonyl -carbapenem; PA0 (5R,6S)-2-(2-aminoethanethio)-6-(R-1-hydroxyethyl)-3-benzylphosphonyl-carba penem; PA0 (5R,6S)-2-(2-aminoethanethio)-6-(R-1-hydroxyethyl)-3-phosphonyl-carbapenem; PA0 (5R,6S)-2-N,N-dimethylcarbamimidoylmethylthio-6-(R-1-hydroxyethyl)-3-methyl phosphonyl-carbapenem; PA0 Potassium(5R,6S)-2-(2-cyanoethyl)thio-6-(R-1-hydroxyethyl)-3-methylphosphon yl-carbapenem; PA0 (1R,5R,6S)-1-methyl-2-(2-aminoethanethio-6-(R-1-hydroxyethyl)-3-methylphosp honyl-carbapenem; PA0 Potassium(1R,5R,6S)-1-trifluoromethyl-2-(2-acetamido)thio-6-(R-1-hydroxyeth yl)-3-benzylphosphonyl-carbapenem; PA0 Potassium(5R,6S)-2-ethylthio-6-(R-1-hydroxyethyl)-3-methylphosphonyl-carbap enem; PA0 Potassium(5R,6S)-2-[(N-acetyl)aminoethylene]thio-6-(R-1-hydroxyethyl)-3-met hylphosphonyl-carbapenem; PA0 Potassium(5R,6S)-2-cyanomethylthio-6-(R-1-hydroxyethyl)-3-pivaloyloxymethyl phosphonyl-carbapenem; PA0 (1R,5R,6S)-1-amino-2-(3-S-(N-acetamidine)-pyrrolidinyl)thio-6-(R-1-hydroxye thyl)-3-methylphosphonyl-carbapenem; PA0 sodium(5R,6S)-3-phenylthio-6-(R-1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-e n-7-one-2-dimethylphosphonate; PA0 sodium(5R,6S)-3-cyanomethylthio-6-(R-1-hydroxyethyl)-1-azabicyclo[3.2.0]hep t-2-en-7-one-2-methylphosphonate; and PA0 potassium(5R,6S)-3-cyanomethylthio-6-(R-1-hydroxyethyl)-1-azabicyclo[3.2.0] hept-2-en-7-one-2-benzylphosphate. PA0 sodium(5R,6S)-3-phenylthio-6-(R-1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-e n-7-one-2-dimethylphosphonate; PA0 sodium(5R,6S)-3-cyanomethylthio-6-(R-1-hydroxyethyl)-1-azabicyclo[3.2.0.]he pt-2-en-7-one-2-methylphosphonate; and PA0 potassium(5R,6S)-3-cyanomethylthio-6-(R-1-hydroxyethyl)-1-azabicyclo[3.2.0] hept-2-en-7-one-2-benzylphosphonate.
Preferably, R.sup.1 is hydrogen, methyl, ethyl, amino, --NHCOCH.sub.3, hydroxyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxymethyl, carboxy or trifluoromethyl; R.sup.2 is methyl, ethyl, cyanomethyl, cyanoethyl, aminoethyl, --CH.sub.2 CH.sub.2 NHCH.dbd.NH, phenyl substituted with at least one substituent wherein the substituents are selected from amino, --NHCOCH.sub.3, --NHCH.dbd.NH, aminomethyl, nitro, halo, methyl, ethyl or trifluoromethyl, 3-pyrrolidinyl, 3-pyrrolidinyl substituted with --CH.dbd.NH or ##STR7## 2-pyrrolidinyl, N-substituted 2-pyrrolidino wherein the substituent is --CH.dbd.NH or ##STR8## 3-.DELTA..sup.1 -2-amino-pyrrolidinyl, 3-.DELTA..sup.1 -2-amino-piperidinyl, or N,N-dimethylcarboxamidine; and R.sup.3 is hydrogen, a metal cation, methyl, ethyl, benzyl, ##STR9## wherein R.sup.5 is hydrogen, methyl, or tert-butyl, and M is a metal cation or H.sup.+.
Most preferably, R.sup.1 is hydrogen, methyl, ethyl, amino, --NHCOCH.sub.3, hydroxyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxymethyl, carboxy or trifluoromethyl; R.sup.2 is cyanomethyl, cyanoethyl, 2-aminoethyl, --CH.sub.2 CH.sub.2 NHCH.dbd.NH, 3-pyrrolidinyl, 3-pyrrolidinyl substituted with --CH.dbd.NH or ##STR10## 2-pyrrolidinyl, N-substituted 2-pyrrolidinyl wherein the substituent is --CH.dbd.NH or ##STR11## 3-.DELTA..sup.1 -2-amino-pyrrolidinyl, 3-.DELTA..sup.1 -2-amino-piperidinyl, N,N-dimethylcarboxamidine, or phenyl substituted with a substituent selected from amino, --NHCOCH.sub.3, --NHCH.dbd.NH, aminomethyl, nitro or halo; and R.sup.3 is hydrogen, a metal cation, methyl, ethyl, benzyl, methyl, ethyl, benzyl, ##STR12## wherein R.sup.5 is hydrogen, methyl or tert-butyl and M is a metal cation or H.sup.+.
The aforementioned alkyl groups may have chain, branched and cyclic structures. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and cyclohexyl.
The term metal cation is used herein means a pharmaceutically acceptable alkali or alkaline earth metal cation. Examples of such cations are sodium, potassium, calcium and magnesium. Preferably, M is sodium or potassium.
The present invention also relates to processes for the preparation of said carbapenems, pharmaceutical compositions comprising such compounds, and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
The carbapenems of the present invention may have various optical isomers. Preferred isomers have the structure: ##STR13## wherein R.sup.1, R.sup.2, R.sup.3 and M.sup.+ are as defined above.
Illustrative examples of compounds of the present invention are the following:
The following are preferred compounds of the present invention:
The preparation of compounds of the present invention is illustrated by the following reaction scheme: ##STR14##
A chiral beta-lactam starting intermediate III, possessing all three asymmetric centers in the desired configuration is reacted with lithiomethyldimethylphosphonate to give the keto-phosphonate IV. This first reaction is the only carbon-carbon bond formation required. Diazo-transfer proceeds rapidly with p-dodecylbenzenesulfonylazide and diazobicycloundecene (DBU) as base to yield V. Refluxing V with a catalytic amount (about 1% by weight) of rhodium acetate dimer in dichloromethane gives pure VI after simple filtration. Triflation of the C-2 oxygen of VI with DBU and N-phenyltrifluoromethanesulfonimide or freshly distilled trifluoromethanesulfonic anhydride yields VII. Treatment of VII with thiophenol and N-p-nitrobenzyloxycarbonylcysteamine gives VIIIa and VIIIb. Addition of sodium hydrogen-sulfide to the triflate solution followed by chloroacetonitrile provides VIIIC. After desilylation, VIIIa-c are mono-demethylated with several equivalents of sodium iodide in acetone at reflux. Products IXa, IXb and IXc are isolated by reverse-phase preparative thin layer chromatography of the evaporated reaction mixture. Hydrogenation of IXb gives 3-methylphosphonyl thienamycin IXd.
Preparation of compounds of the present invention wherein R.sup.1 is other than hydrogen is illustrated by the following reaction scheme: ##STR15##
Compounds of the Formula III are prepared from compounds IIIa by an appropriate reaction. For example, IIIa is treated at low temperature in a solvent such as tetrahydrofuran, diethylether, or dioxane, with a strong base, such as lithium diisopropylamide, potassium tert-butoxide, or sodium hexamethyldisilazide, followed by an appropriate reagent such as methyl iodide (R.sup.1 =CH.sub.3), bromine (R.sup.1 =Br) or carbon dioxide (R.sup.1 =CO.sub.2 H) to give the desired Compound III. Certain compounds of the Formula III can be used as intermediates in preparing other compounds. For example, Compound III where R.sup.1 is bromine can be converted to the compound where R.sup.1 is amino by reaction with sodium azide and dimethylformamide and reduction by hydrogenation.
The novel compounds are valuable antibiotics active against various gram-positive and gram-negative bacteria and, accordingly, find utility in human and veterinary medicine. The compounds of this invention may therefore be used as antibacterial drugs for treating infections caused by gram-positive or gram-negative bacteria, for example, against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia, Pseudomonas aeruginosa, Enterobacter, Enterococcus, and Bacterium proteus. The antibacterials of the invention may further be utilized as additives to animal feeds, for preserving foodstuffs and as disinfectants. For example, they may be employed in aqueous compositions in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy and inhibit one growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example, in waterbased paints and in the white of paper mills to inhibit the growth of harmful bacteria.
The products of this invention may be used alone or in combination as an active ingredient in any one of a variety of pharmaceutical preparations. They may be combined with other drugs to provide compositions having a broad spectrum of activity. These antibiotics may be employed in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They may be administered orally, topically or parenterally by injection (intravenously or intramuscularly).
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example, lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycine; lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica; disintegrants, for example, potato starch or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of aqueous of oily suspensions, solutions, emulsions, syrups, elixirs, etc. or may be presented as a dry product, for reconstitution with water or other suitable vehicles before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methyl cellulose, glycose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible oils, for example almond oil, fractionated coconut oil, oily esters, propylene glycol, or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. Suppositories will contain conventional suppository base, e.g. cocoa butter or other glyceride.
Compositions for injection may be presented in unit dose form in ampules, or in multidose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
The compositions may also be prepared in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently take the form of powder or liquid sprays or inhalants, lozenges, throat paints, etc. For medication of the eyes or ears, the preparations may be presented as individual capsules, in liquid or semi-solid form, or may be used as drops etc. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, powders, etc.
Also, in addition to a carrier, the instant compositions may include other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricators, suspending agents, viscosity agents or flavoring agents and the like. In addition, there may also be included in the composition other active ingredients to provide a broader spectrum of antibiotic activity.
For veterinary medicine the composition may, for example, be formulated as an intramammary preparation in either long or quick-release bases.
The dosage to be administered depends to a large extent upon the condition and size of the subject being treated as well as the route and frequency of administration, the parenteral route being preferred for generalized infections and the oral route for intestinal infections. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the chosen species of this invention. In general, a daily oral dosage consists of from about 2 to about 600 mg of active ingredient per kg of body weight of the subject in one or more applications per day. A preferred daily dosage for adult humans lies in the range of from about 15 to 150 mg of active ingredient per kg of body weight.
The instant compositions may be administered in several unit dosage forms as, for example, in solid or liquid orally ingestible dosage form. The compositions per unit dosage, whether liquid or solid may contain from 0.1% to 99% of active material, the preferred range being from about 10 to 60%. The composition will generally contain from about 15 mg to about 1500 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 100 mg to 1000 mg. In parenteral administration the unit dosage is usually the pure compound in a sterile water solution or in the form of a soluble powder intended for solution. Consideration of individual properties of solubility and stability well determine the optimum pH of such a solution. The pH will generally be in range of 5.5 to 8.2.
The following Examples illustrate but do not limit the product, process, compositional or method of treatment aspect of the present invention. All temperatures are in .degree.C.